Liver Function Tests Functions of the liver Carbohydrate and Lipid - PowerPoint PPT Presentation

Liver Function Tests

Functions of the liver ► Carbohydrate and Lipid metabolism  Gluconeogenesis / Glycogenolysis / Glycogenesis  Cholesterol and triglyceride production ► Synthetic function  Amino acids processing and formation  Protein synthesis ► albumin, ► coagulation factors ( fibrinogen, prothrombin, V, VII, IX, X and XI), ► anticoagulants (protein C, protein S, antithrombin) ► acute phase proteins  Bile acids ( fat digestion)  Heparin (anti-coagulant)  Hormone production ► somatomedins (promote growth in bone, soft tissues) ► angiotensinogen ► ILF-1 ► thrombopoietin

Functions of the liver ► Storage Capacity  Glycogen, vitamins A, B 12 , D, E, K, iron, copper ► Metabolism of waste products / toxins  Deamination of amino acids / Ammonia processing  Phase 1 / Phase 2 reactions ► Immune function  Reticulo endothelial function ► Kupffer cells  IgA into digestive tract

Anatomy

Liver problems on the wards ► Sepsis ► Drug overdose / poisoning ► Trauma  Accidental / Post liver resection ► Alcoholism ► Jaundice  Hepatitis  Cholecystitis ► Variceal bleeding 2 portal hypertension ► Spontaneous bacterial peritonitis

Liver function tests ► Confusing  Lots of them  Dynamic - can change rapidly  Not specific  When high might be normal  When low might be bad  When normal liver might be sick  Involves metabolic pathways I can’t remember

Tests ► LFTs – enzymes AST ALT GGT ALP ► Synthetic function  Total protein / Albumin / prothrombin time ► Metabolism  Bilirubin / glucose levels ► Markers of liver disease  Sodium, urea, glucose, lactate, ammonia

What to do? ► History ► Examination ► Investigation ► Patterns – indicative of disease process M C Escher ( Dutch graphic artist : 1898 – 1972), Known for mathematically inspired prints with impossible constructions, explorations of infinity, architecture, and tessellations.

Aminotransferases ► involved with amino acid metabolism ► allow transamination,  converts an amino acid into its oxoacid by transfer of an amino (-NH2)  require pyridoxal phosphate as a coenzyme.

Aminotransferases ► Liver  2 aminotransferases  cytoplasmic and mitochondrial ► ALT predominantly hepatic ( cytosol ), ( negligible in heart/muscle/kidneys) ► AST (mitochondria and cytosol) in liver,  also in muscles (cardiac and skeletal) , kidney, pancreas and erythrocytes ► ALT and AST are released from liver when hepatocytes are damaged or destroyed

What to do? ► History ► Examination ► Investigation ► Patterns – indicative of disease process ► If doubt measure another enzyme e.g. CK / TN ► Organise imaging/test

ALT - Alanine Transaminase ► Enzyme  Converts amino acid into pyruvate ► Predominantly in liver,  also in skeletal muscle, kidneys and heart ► Located in cytosol  Spilled out into plasma as liver cells die  Usually higher than AST  Good marker of liver inflammation  Can be normal in sick liver  In alcoholic liver disease usually lower than AST

ALT > AST (normal) AST > ALT ETOH disease

ALT normal in sick liver

ALT and disease ► Very high levels ( upto x50 normal)  Severe necrosis, severe viral or drug induced hepatitis ► Moderately high levels  EBV, chronic hepatitis, cholestasis, early or improving acute viral hepatitis, CCF with hepatic congestion ► Slight-to-moderate elevations  (usually with higher increases in AST levels)  insult producing acute hepatocellular injury, eg active cirrhosis, and drug-induced or alcoholic hepatitis ► Marginal elevations  acute MI, (hepatic congestion or ALT from heart)

AST ► Two isoenzymes are present In humans:  GOT 1 - cytosolic red blood cells / muscles cytoplasm / kidneys  GOT 2 - liver mitochondria and cytosol

ALT and AST ► In general,  increases in AST and ALT are higher with viral or toxin hepatitis than with biliary obstruction  in viral hepatitis levels may rise upto 14 days before jaundice ► Cholestasis will increase ALT and AST when associated with hepatocellular death

Typical AST/ALT Values in Disease Aminotransferases often normal in cirrhosis. In uncomplicated alcoholic hepatitis, AST normally less than 500 U per L The highest peak aminotransferase values are found in patients with acute ischemic or toxic liver injury.

Rules of thumb The higher the AST : ALT ratio, greater likelihood 1. alcohol contributing to abnormal LFTs In alcohol the ratio is normally 2:1  elevated AST : ALT ratio in alcoholic liver disease results from  the depletion of vitB6 (pyridoxine), needed as a cofactor In the absence of alcohol intake, increased AST : ALT 2. ratio often found in patients with cirrhosis ALT level > 500 IU/L unlikely to be just alcoholic liver 3. disease AST:ALT ratios are suggestive of certain conditions but 4. ratio cannot be totally relied on

ALP – alkaline phosphatase ► Enzyme which dephosphorylates substrates  Eg proteins, nucleotides, in an alkaline environment  May have role in regulating biliary secretions ► Found in all tissues  predominantly liver ( bile duct 55%),  bone ( osteoblasts 45%),  gut (5%) / kidney / placenta ► Isoforms exist –  ALP I intestinal 5%  ALP L tissue non specific (Liver/Kidney/Bone)  ALP P placental

Elevated ALP ? normal = 20 – 140 iu / l ► differentiate source ► are other LFTs elevated including bilirubin?  (electrophoresis / heat exposure) bone burns, liver lasts ► Higher ALP levels may be due to:  Biliary obstruction / Liver disease  Bone disease - Healing fracture / Osteoblastic bone tumors / Osteomalacia / Paget's / Rickets  Hyperparathyroidism  Leukemia / Lymphoma  Sarcoidosis  Fatty meal ingestion (blood type O or B)

Obstructive picture

Gamma glutaryl transferase ► Catalyst for transport of gamma glutaryl group from glutathione found at cell membranes ► Actual role unclear BUT  Glutathione - free radical scavenger involved in detoxification ► Found in hepatocytes and biliary epithelial cells ► Used as “ESR” of the liver ► Increase in alcoholics and obstructive biliary disease  unclear why elevated in alcoholics  possible induction of enzymes / leakage from cells / increased oxidative stress  may be elevated on its own in drinkers

Alcoholic hepatitis

Obstructive picture

Jaundice

Bilirubin ► Processing involves three steps 1. Absorption 2. Conjugation 3. Excretion Rate limiting step is excretion  Often conjugated form in liver diseases 

Causes of jaundice ► Unconjugated Bilirubinaemia < 20% bilirubin is conjugated  1) Overproduction - ► Haemolysis / rhabdomyolysis / ineffective erythropoiesis 2) Decreased hepatic conjugation - ► Heme enters liver, converted to bilirubin, but not conjugated ► Bilirubin builds up blood and is filtered by the kidneys into urine Causes  Gilberts syndrome (mild drop glucuronyl transferase) 1. Crigler - Najar syndromes 2. Hepatitis - viral and drugs 3.

Causes of jaundice ► Conjugated Bilirubinaemia  > 50% bilirubin is conjugated ► Impaired intrahepatic secretion  Hepatocellular disease  Sepsis  Cholestasis of pregnancy  Drug induced IVN / Clavulinic acid / flucloxacillin / carbamazepine OCP / erythromycin  Infiltrative processes (amyloid / sarcoid) ► Impaired extraheptic clearance  Mechanical obstruction ( stones/tumour)

Gilberts Syndrome

Acute Liver failure ► Hyperacute  onset of encephalopathy <7 days of jaundice ► Acute  encephalopathy within 8 – 28 days of jaundice ► Subacute  encephalopathy within 4 – 26 weeks O’Grady, Lancet 1993

Causes of acute liver failure ► Viral ► Drugs / Toxins ► Vascular events ► Others  pregnancy / Wilsons / lymphoma / trauma / heat stroke

Overdoses / Poisoning

Hyperacute Liver Failure - Mushrooms

Paracetamol toxicity in chronic liver disease

Paracetamol toxicity

Trauma

Lactate ► Type A - Hypoxic  Reduced oxygen / perfusion – ► Liver failure / sepsis ► Type B – Nonhypoxic  1) disease states : Sepsis / Liver disease / thiamine deficiency  2) drugs – metformin / ethanol / paracetamol  3) metabolic disorders – mitochodria eg G6PD / MELAS /

Mitochondrial disease - MELAS mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes

Prothrombin time ► does not become abnormal until more than 80% of liver synthetic capacity is lost ► PT a relatively insensitive marker of liver dysfunction  only based on manufacture of clotting factors and dependent on vit K stores ► Often useful for following liver function in patients with acute liver failure

Liver failure and prothrombin time

Liver failure and INR

Hepatic encephaolpathy